ABSTRACT ? BIOMARKER CORE The primary objective of the newly configured Biomarker Core (BC) is to collect, bank, and distribute biofluids in order to generate biomarker datasets that will address disease heterogeneity and clinical transitions to subjective cognitive decline (SCD), mild cognitive impairment (MCI) and early stages of Alzheimer's disease (AD), with the long term goal of developing novel interventions that will delay or prevent these transitions. During its more than 25 years of continued funding, the NYU ADRC has been in the forefront of improving diagnostic tools and defining preclinical and prodromal stages of AD. In this renewal period, the dedicated BC will be reconfigured to serve as a conceptual and technical core for established investigators and the next generation of students and neuroscientists; and, to foster the use of plasma, serum and cerebrospinal fluid (CSF), as well as stool samples for microbiome analyses, to understand biological mechanisms of disease progression and heterogeneity. We propose the following Aims. In Aim 1, we will coordinate intake, processing and storage of biofluids from Clinical Core (CC) participants in association with the Data Management & Statistics (DMS) Core. In Aim 2, we will perform state-of-the-art analysis of known blood and CSF biomarkers for the diagnosis, prognosis, and prediction of AD. Assays will include, but will not be limited to, A?40/42/38, phosphorylated/total tau and neurofilament light-chain, all within the new amyloid/tau/neurodegeneration (ATN) framework, in addition to markers of cerebrovascular disease, inflammation, glial activation, as well as biological variables such as age, sex, ApoE4, and sleep (among others), which will be key to increase our understanding of disease heterogeneity. In Aim 3, we will use Simoa technology to develop novel ultrasensitive biomarker assays, guided in part by proteomic findings by the Neuropathology (NP) Core and other emerging data from the ADRC network. Aim 4 is designed to manage samples, perform quality control and analyses as well as link sample information obtained through the DMS, CC, Neuroimaging (NIC), and NP Cores. As part of Aim 5, we will share biosamples with NCRAD and other research collaborative efforts within NYU (e.g. NYU Metabolomics Lab) and outside collaborators from other ADRC (e.g. Microbiome Project). Last, in Aim 6, we will collaborate with other ADRCs to harmonize and optimize biomarker assays across centers. In summary, the BC will perform state-of-the-art biofluid biomarker analyses within the new ATN framework, and work with the NIC and CC cores to help understand disease heterogeneity and stage transitions to SCD, MCI, and AD. Further, it will help harmonize multiple biomarker assays and develop scientific discovery of novel ultrasensitive biomarkers for AD.